Molecular Mechanisms of the Genetic Predisposition to Acute Megakaryoblastic Leukemia in Infants With Down Syndrome

Juliane Grimm; Dirk Heckl; Jan-Henning Klusmann

doi:10.3389/fonc.2021.636633

Molecular Mechanisms of the Genetic Predisposition to Acute Megakaryoblastic Leukemia in Infants With Down Syndrome

Front Oncol. 2021 Mar 11:11:636633. doi: 10.3389/fonc.2021.636633. eCollection 2021.

Authors

Juliane Grimm^{1

2}, Dirk Heckl¹, Jan-Henning Klusmann¹

Affiliations

¹ Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.
² Department of Internal Medicine IV, Oncology/Hematology, Martin Luther University Halle-Wittenberg, Halle, Germany.

Abstract

Individuals with Down syndrome are genetically predisposed to developing acute megakaryoblastic leukemia. This myeloid leukemia associated with Down syndrome (ML-DS) demonstrates a model of step-wise leukemogenesis with perturbed hematopoiesis already presenting in utero, facilitating the acquisition of additional driver mutations such as truncating GATA1 variants, which are pathognomonic to the disease. Consequently, the affected individuals suffer from a transient abnormal myelopoiesis (TAM)-a pre-leukemic state preceding the progression to ML-DS. In our review, we focus on the molecular mechanisms of the different steps of clonal evolution in Down syndrome leukemogenesis, and aim to provide a comprehensive view on the complex interplay between gene dosage imbalances, GATA1 mutations and somatic mutations affecting JAK-STAT signaling, the cohesin complex and epigenetic regulators.

Keywords: ML–DS; TAM; Trisomy 21 (Down syndrome); acute megakaryoblastic leukemia; acute myeloid leukemia; genetic predisposition; transient myeloproliferative disorder of Down syndrome.

Publication types

Review